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The nature of chromosome segregation errors in the early mitotic divisions of human embryos
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Ford, Emma (2021) The nature of chromosome segregation errors in the early mitotic divisions of human embryos. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3748126
Abstract
Every single one of the ~50 million cells that constitute a human being originates from serial divisions of the zygote – the fertilised egg that brings maternal and paternal genomes together for the first time. Surprisingly, over half of human embryos are aneuploid indicating that chromosomes must be erroneously segregated during the early mitotic divisions. This can also create mosaic embryos, containing karyotypically different cell lineages. However, the types of errors and mechanisms leading to aneuploidies are unknown in early human embryos as these events have never been imaged in live embryos.
In this study I imaged chromosome movements during the first two mitotic divisions of human embryos. I show that mitosis I is extended compared to somatic cells and error-prone with embryos displaying lagging chromosomes, multipolar chromosome segregation and micronuclei. These errors appear to be maternal age independent. This is in contrast to the second mitotic division which is shorter and mostly bipolar, with much fewer lagging chromosomes, putting forward the uniquely erroneous nature of the first mitotic division.
Crucially, this data is based on fresh normally fertilised human embryos thanks to our egg sharer program, as well as on fresh human oocytes and embryos donated to research as they could not be used for IVF or ICSI treatment, which I term deselected. Comparing embryos from different sources as well as clinical embryos showed that deselected embryos are a robust model when it comes to studying early human embryonic development.
I also show that the spindle assembly checkpoint (SAC) is not responsible for setting the timing to anaphase onset, instead it could be an intrinsic timing mechanism which is responsible for triggering anaphase. I thus hypothesise that a 12 weak SAC, which is normally responsible for holding a mitotic cell in metaphase until all the chromosomes are aligned on the metaphase plate, could be at the origin of the high aneuploidy rates of human embryos.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics | ||||
Library of Congress Subject Headings (LCSH): | Human embryo, Mitosis -- Research, Chromosomes, Fertilization (Biology) | ||||
Official Date: | July 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Hartshorne, Geraldine M. ; McAinsh, Andrew D. | ||||
Format of File: | |||||
Extent: | 175 leaves : illustrations | ||||
Language: | eng |
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